Evaluation of the sedative and physiological effects of xylazine, detomidine, medetomidine and dexmedetomidine in goats

Abstract Background Many α2‐agonists are commonly used for sedation and analgesia in ruminants. Introduction The present study aims to compare the sedative and physiological effects of intravenous (IV) administration of xylazine, detomidine, medetomidine and dexmedetomidine in goats. Methods Ten healthy goats aged 6 ± 1 months and weighing 15 ± 2 kg were used in experimental, crossover Latin square, randomised and blinded study. Animals were assigned to five IV treatments: control (normal saline); xylazine (100 μg kg−1); detomidine (50 μg kg−1); medetomidine (20 μg kg−1) and dexmedetomidine (5 μg kg−1). The degree of sedation was investigated using a numerical ranking scale of 0–10. Sedation scores were compared at each time using nonparametric (Kruskal–Wallis and Mann–Whitney U) tests. Results Heart rate (HR), respiratory rate (RR), rectal temperature (RT), ruminal motility and capillary refill time (CRT) were performed before (baseline) and after drug administration. Animals in α2‐adrenergic agonist treatments were sedated at 5–60 min. There were no significant differences among α2‐adrenergic agonist treatments at 5–60 min in sedation scores. HR significantly decreased from baseline 5–90 min after α2‐adrenergic agonists’ administration. Ruminal motility was decreased in α2‐adrenergic agonist treatments at 5, 90 and 120 min and absent at 10–60 min. A significant decrease from baseline in RR was detected between 30 and 90 min after α2‐adrenergic agonists’ administration. RT was unchanged in any treatment for 120 min. CRT was less than 2 s at all time points following each treatment. Conclusions The duration of sedation was up to 60 min after IV administration of xylazine (100 μg kg−1), detomidine (50 μg kg−1), medetomidine (20 μg kg−1) and dexmedetomidine (5 μg kg−1) in goats in this study. No significant differences were detected between xylazine, detomidine, medetomidine and dexmedetomidine in goats.


INTRODUCTION
In addition to physical restraint, chemical agents are useful and often necessary to ensure immobility and to provide sedation and analgesia for surgical and non-surgical procedures in the veterinary patients (Kästner, 2006). Many α 2 -agonists and narcotics are commonly used for sedation, analgesia and anaesthesia in ruminants (Kästner et al., 2007;Kutter et al., 2006).
Since there is a distinct lack of documented information on the sedative effects of α 2 -adrenergic agonists in goats, the present study aimed to compare the effects of intravenous (IV) administration of xylazine, detomidine, medetomidine and dexmedetomidine on sedation and some physiological variables in goats. The hypothesis of this study is that the sedative and physiological effects would vary between α 2 -adrenergic agonists in goats.

Animals
The study was approved by the animal welfare committee of the Fac- Prior to the experiment, food and water were withheld from the goats 12 and 6 h respectively. The experiment was carried out in the morning. The animals were weighed before each treatment performed for calculation of drug dosages. Two animals were studied at any one time. The animals were unable to see or interact with each other. The Skin over the left jugular vein was prepared aseptically for IV administration. The animals were gently restrained on the special bed (on top of a soft mattress) in a quiet, covered, 5 × 6 m 2 area and rested for 20 min before first measurement of physiological variables were recorded.

Experimental procedures
The goats were assigned to five IV treatments in a randomised (computer-generated)

Sedation scores
Three independent observers (who were unaware of the drug type and dose) assessed the degree of sedation for each animal.  De Carvalho et al., 2016;Kästner et al., 2003). The final sedation score for each animal was considered the majority score which the observers gave to each animal. Sedation scores were recorded before other measurements at the following times: baseline (before drug administration, time 0) and at 5, 10, 15, 30, 45, 60, 90 and 120 min, resulting in nine time points for each animal.

Physiological variables
Physiological variables including HR, RR, RT, CRT and ruminal motility were recorded at the same time points as the sedation was recorded.

Statistical analysis
A prospective power calculation (G * Power Version 3.1.9.2) conducted on the basis of information reported elsewhere De Carvalho et al., 2016) determined that a total of ten animals were required (α of 0.05 and β of 0.2) to detect a 20% difference between treatments. Data were analysed using SPSS software version 20 (SPSS for Windows, SPSS Inc, Chicago, Illinois, USA). Before any statistical analysis, distribution of data was performed for normality using the Kolmogorov-Smirnov test and normality of data distribution was verified. Sedation scores and physiological variables were expressed as median (range) and mean ± standard deviation, respectively. Sedation scores were compared at each time using nonparametric (Kruskal-  Altman (1990). A p value of less than 0.05 was considered significant.

RESULTS
All the goats had recovered by 3 h based on behavioural sings such as standing, head up, head and ear movement, consciousness and responsiveness. The inter-rater agreement among the observers was very good (k = 0.92; p < 0.05). Different physiological variables are demonstrated in Table 1. All animals in control showed no sedation at any time point. Animals in α 2 -adrenergic agonist treatments were sedated at 5-60 min (Table 1). Just one animal in each α 2 -adrenergic agonist treatment achieved sedation score 1 at 90 and 120 min. Sedation was higher in α 2 -adrenergic agonist treatments than in control at 5-60 min after drug administration (p < 0.05). There were no significant differences among α 2 -adrenergic agonist treatments at 5-60 min in sedation scores.
HR significantly decreased from baseline at 5-90 min after α 2adrenergic agonists' administration. HR was significantly lower in α 2adrenergic agonist treatments than control at 5-90 min after drug administration (p < 0.05). A significant decrease from baseline in RR was detected between 30-90 min after administration of α 2adrenergic agonists. Compared to control, RR was significantly lower in α 2 -adrenergic agonist treatments at 30-90 min after drug administration. Ruminal motility was decreased in α 2 -adrenergic agonist treatments at 5, 90 and 120 min and absent at 10-60 min. Compared to control, ruminal motility was significantly lower in α 2 -adrenergic ago-nist treatments at 5-120 min after drug administration. There were no significant differences in HR, RR and ruminal motility among α 2adrenergic agonists at all time points. RT was unchanged in any treatment for 120 min. CRT was less than 2 s at all time points following each treatment.

DISCUSSION
α 2 -adrenergic agonists are used for sedation in small ruminants (Kästner, 2006). These drugs bind to α 2 -agonist receptors in the brain and spinal cord (Kästner et al., 2003). The xylazine and medetomidine doses used in the present study were determined based on other studies in sheep (De Carvalho et al., 2016;Kästner, 2006). Medetomidine at 20 μg kg −1 is recommended in goats by Carroll et al. (2005). The dexmedetomidine dose used in the present study was determined based on other study in sheep . It would not regard that the doses used in this study as equipotent. Medetomidine contains 50% active dexmedetomidine, so 20 μg kg −1 medetomidine should be twice as potent as 5 μg kg −1 dexmedetomidine. In this experiment, dexmedetomidine (at 5 μg kg −1 ) appeared to be at least as potent as medetomidine (at 20 μg kg −1 ). According to the results, the hypothesis of this study was disproved and there is no significant differences were detected between α 2 -adrenergic agonists in goats. It may be due to the doses and pharmacological characteristics of α 2 -adrenergic agonists used in this study (Celly et al., 2003;Kästner, 2006).
α 2 -adrenergic agonists suppress the vasomotor centre in brainstem in the central nervous system (CNS). Sedation is associated with decrease in sympathetic outflow from the CNS (Pawde et al., 1996). In this study, animals in α 2 -adrenergic agonist treatments were sedated at 5-60 min. In a study carried out in sheep, treatment with 30 μg kg −1 detomidine, 10 μg kg −1 medetomidine or 100 μg kg −1 xylazine resulted in sedation lasting 60 min (Celly et al., 2003). Administration of 100 μg kg −1 xylazine  or 5 μg kg −1 dexmedetomidine (De Carvalho et al., 2016) in sheep was reported to produce sedation lasting 90 min. It should be noted that sex, age, species and breed, rout of administration and also other factors including environmental variables may affect the sedation in farm practice (Kästner et al., 2003). Good sedation is important to perform clinical procedures (surgical and non-surgical) efficiently and properly. Veterinarians can do a better job when the animal is not moving, struggling and/or vocalising (Seddighi & Doherty, 2016). In this study, no significant differences were detected among α 2 -adrenergic agonists in sedation scores. However in the country the experiment took place, xylazine is readily available and very inexpensive, while detomidine and dexmedetomidine are much more expensive. Medetomidine is not readily available anymore.
All α 2 -adrenergic agonists in this study a significant reduction in HR 5-90 min after drug administration. Pawde et al. (1996) reported to produce bradycardia for 90 min by 15 μg kg −1 medetomidine in goats. Administration of 5 μg kg −1 dexmedetomidine was reported to produce bradycardia for 120 min in sheep .

TA B L E 1 Comparison of xylazine, detomidine, medetomidine and dexmedetomidine on sedation scores [median (range)] and physiological variables (mean
± standard deviation) in ten goats.
Assessment of only HR and RR are inadequate to describe the cardiorespiratory effects of these drugs. Evaluation of stroke volume, blood pressure, pulmonary arterial pressure, pH and partial pressures of arterial oxygen and carbon dioxide would describe the effects of these drugs.

ACKNOWLEDGMENTS
I would like to thank Dr. Marzieh Karimiafshar for assistance with English language editing.

CONFLICT OF INTEREST
The authors declare that they have no competing interests.

ETHICAL APPROVAL
All ethical considerations including utilising animals were considered cautiously. The trial convention was affirmed by the animal welfare committee (which was covered IACUC approval) of the Faculty of Veterinary Medicine, Shahid Bahonar University of Kerman, Kerman, Iran (institutional approval number IR.UK.VETMED.REC.1399.014).
All applicable international, national and/or institutional guidelines for the care and use of animals were followed.

DATA AVAILABILITY STATEMENT
The data that support the findings of this study are available from the corresponding author upon reasonable request.